Received 03/02/2014 Review began 03/03/2014 Review ended 04/04/2014 Published 04/06/2014

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Engineering Magnetic Nanoparticles forThermo-Ablation and Drug Delivery inNeurological CancersAyden Jacob , Krishnan Chakravarthy

1. Director of Translational Medicine, Nanoaxis LLC, Neuroscientist, Neuro-Nanotech Division, Universityof California, Berkeley, Department of Bioengineering 2. CEO, NanoAxis, LLC, The Johns Hopkins Hospital

Corresponding author: Krishnan Chakravarthy, kvc1008@gmail.com Disclosures can be found in Additional Information at the end of the article

AbstractNanobiotechnology involves the engineering of systems, devices, and materials which can beimplemented within a physiological system on a scale between 1-100nm. Nanometric materialshave significant potential to exhibit unprecedented capacities for interacting with specificmolecular, organellar, and cellular components of the brain via their novel optical, electronic,and structural properties. Hence, they are poised to establish new paradigms for the future ofbrain cancer treatment. Nanooncology is currently the most important arena in nanomedicine,and the application of nanoscale innovations in neuroscience will bring forth diagnostic andtherapeutic inventions unseen hitherto in the assessment and treatment of brain cancer.Nanobiosensors, magnetic nanoparticles, and nanoparticle-chemotherapy conjugates are specificavenues within brain cancer treatment that illustrate the credible utilization of sophisticatednanobiotechnology in neurooncology. Nanotechnologically-based medical solutions are slowlyprogressing from the laboratory bench to clinical trials. This review aims to highlight the datathat bridges the gap between laboratory benchtop and hospital bedside, as well as to illustratepotential platforms through which nanomedicine may be integrated into standardized treatmentprotocols against various forms of neurological cancers.

Categories: Miscellaneous, General Surgery, OncologyKeywords: glioblastoma multiforme, nanomedicine, nanotechnology, oncology, neurooncology, drugdelivery, magnetic nanoparticles, brain cancer

Introduction And BackgroundIntroduction to nano-oncologyTumor malignancies originating in the central nervous system (CNS) account for only 2% of allcancers but are correlated with a high mortality and morbidity rate. In 2013, the National CancerInstitute reported over 23,000 new cases of CNS resident tumors and 14,080 deaths that wereattributed to brain tumors [1]. Despite improvements in cancer diagnostics and therapeutics, thefive-year survival rate for both localized and distant CNS tumors remains at a mere 35%.Astoundingly, since 1975, the five-year survival rate has only increased from 22.8% to 34.3% [1].In excess of 50% of the patients who were diagnosed with CNS tumors in 2013 were expected todie from the disease, with a median survival rate of one year [2]. Glioblastoma multiforme (GBM),a primary brain tumor, demonstrates the necessity for innovation in neurooncology treatment.As one of the greatest challenges for neurosurgery and oncology of our century, there iscurrently no cure for GBM, and its phenotypic symptoms are devastating. According to Jain, etal., the deficiencies in the ability to treat GBM are mostly attributed to the lack of our knowledgeof the pathophysiology of GBM, the limited access of chemotherapeutic agents to the site of the

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Open Access Review Article DOI: 10.7759/cureus.170

How to cite this articleJacob A, Chakravarthy K (2014-04-06 14:52:34 UTC) Engineering Magnetic Nanoparticles for Thermo-Ablation and Drug Delivery in Neurological Cancers. Cureus 6(4): e170. DOI 10.7759/cureus.170

brain tumor, the metastatic nature of GBM, and the rapid recapitulation rate of the tumor post-surgical resection [3]. Intense research efforts toward understanding the molecular andbiochemical mechanisms of brain tumors, inclusive of GBM, have provided insights into theelemental processes of these aggressive tumors, but have failed to generate novel solutions inthe realms of chemotherapy, radiation treatment, or surgical procedures. Further, the utilizationof imaging methods to detect the precise location and size of the tumor both pre- and post-resection is imperative in assisting clinicians with the appropriate data needed to makeprognostic treatment decisions (Figure 1). Although the last century has seen little progresstoward a cure for brain tumors, the rapid introduction of biotechnology into the realms ofneuroscience and oncology over the last decade may provide a solution to this intractableproblem.

FIGURE 1: Recurrent Glioblastoma Multiforme

11C-methionine positron emission tomography shows tumor infiltration. Reused with permissionfrom Grosu, et al. and The Intl J Rad Onc Bio Phy [4] (image license #3334690402530).

ReviewNanomedicine and neuro-oncologyThe National Nanotechnology Initiative defines nanotechnology as “the understanding andcontrol of matter at dimensions of roughly 1-100 nm, where unique phenomena enable novelapplications” [5]. Nanoscience enables researchers to study the fundamental building blocks ofnature by creating materials and devices which peer through matter at the nanoscale. Gainingnew insights into physiological systems at the miniscule level of atoms and molecules has givenrise to the field of nanobiotechnology: the application of nanotechnology to the life sciences [6].A result of nanobiotechnology is the development of nanomedicine, a specific field of medicinewhich utilizes the ability to study living cells at the nanoscale in order to implement innovativemethods of diagnostics and therapeutics in medical disease states. An important facet ofnanomedicine today is nanooncology, which is the application of nanobiotechnology inmedicine to study, diagnose, and treat various forms of cancer. Basic brain cancer research isprogressively incorporating nanobiotechnologies to translate hypothetical forms of cancertreatment into innovative nanooncology therapeutics. Nanooncology has produced refinedmethods of microsurgery, new molecular diagnostic techniques, earlier detection of tumors, andenhanced capabilities of the discovery of biomarkers for cancer. Molecular diagnosticimprovements in brain cancer via nanomedicine may propel existing technologies to new heightsof detection capability [5], aid in developing biomarkers in neuronal cancer cells with a higheraffinity for more specific cell receptors in smaller sample volumes [6], and image solid tumorswith a higher rate of specificity by utilizing quantum dots (QDs) and specific elementalnanoparticle forms [7]. Herein, we aim to discuss the future capabilities of nano-neurooncoloy byevaluating recent failures and triumphs in this exciting domain of medicine.

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Nanoparticle drug delivery across the blood brain barrierA specific area within which nanomedicine will have a tangible impact in neurooncologyis through the provision of a novel method by which drugs, genes, and molecules can efficientlycross the blood brain barrier (BBB) with high kinematics and pharmocokinetics. Chemotherapy isconventionally administered orally or intravenously. Pharmacologically active chemoagentstargeting the brain usually reach the tumor with low specificity and, more importantly, dose-limiting toxicity. Oral administration exposes the anti-cancer drug to the metabolic system andcould potentially cause unwanted pharmacokinetics, resulting in decreased tumor reactivity tothe given dose. In parallel to this limitation, intravenously administered chemotherapy has lowspecificity which can be potentially harmful to nearby healthy tissue. Nanoparticle-based drugdelivery may circumvent these common limitations by accessing the brain without exposing theanti-cancer drug to the metabolic system of the host organism. Further, nanoparticle-chemoagent conjugates could potentially be directed to specifically accumulate within the tumorsite, becoming active only within a specific region of the brain, thereby sparing healthy tissuefrom potential toxicities inherent with chemotherapeutic agents.

The control of elemental processes that occur at the molecular level are required in order tooptimize the efficacy of oncology deliverables. The intravenous administration of drugs targetedto neuronal tumors must have the capacity to accurately locate the CNS upon introduction intothe body, without causing systemic side-effects. Subsequently, they must traverse the BBB toexclusively target the tumor cells that they intend to destroy [8]. Ideally, the drug would berestricted to be active only in the regional vicinity of the target, at a specific point in time, andspare its influence on adjacent sensitive brain matter. Indiscriminate collateral damage couldpotentially be catastrophic in that the destruction of healthy brain tissue may interrupt essentialneuronal cicuitry. Simultaneously, the potential benefits to a patient undergoing nanooncologytreatment are significant. The challenge of achieving this ideal scenario includes optimizingelemental processes in engineering, physics, biology, chemistry, and pharmacology (Figure 2).Though these goals have not yet been achieved, a substantial amount of work toward thedevelopment of nanobiotechnology is propelling the biomedical community into an era thatmight realize the success of nanoparticle-enabled chemotherapeutic drug conjugates, which mayefficaciously penetrate the BBB.

FIGURE 2: Nanoparticle Applications

Adapted with permission from Sinha, et al. [9] A: Tumor-activated drug delivery. B: Nanoparticleswith both diagnostic and therapeutic functions.

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In an attempt to deliver anti-tumoric drugs to a mouse model via nanoparticle technologies,Brigger, et al. utilized radiolabeled PEG-coated hexadecylcyanoacrylate nanospheres to target agliosarcoma [10]. This study demonstrated a several-fold increase in the accumulation of thenanospheres within the targeted tumor, in comparison to surrounding brain tissue [10]. Garcia, etal. employed confocal microscopy to confirm that PEG-coated hexadecylcyanoacrylatenanoparticles can translocate successfully across the BBB via endocytosis in a safe mechanisticmanner [11]. The translocation of nanoparticles across the BBB via endocytosis is not the onlymechanism by which nanoparticles succeed at gaining entry to the brain. Silva, et al. states that“By conjugating different ligands to nanoparticle carriers, different transporters could potentiallybe recruited to facilitate the translocation of specific molecules or compounds. For example,nanoparticles composed of polyoxyethylene 21 stearyl ether conjugated with thiamine on theirsurfaces have been shown to cross the BBB via specific interactions with thiamine transporters”[8]. Feng, et al. developed PLGA nanoparticles containing the drug, paclitaxel, and administeredthem in 29 different types of cancer cell lines. In vitro experiments showed a 13-fold increase incytotoxicity in all targeted cancers in comparison to those administered cancers being treatedwithout the nanoparticle conjugate [12]. Of particular interest in this report is the observationthat Feng, et al. were able to utilize different forms of spectroscopy to prove that paclitaxel wasintegrated into the nanoparticle sphere with high efficiency.

For the development of nanobiotechnologies in neurooncology, these techniques are importantin order to ensure the pharmacokinetics of the drug within the brain. Further, Fang, et al.reported that the kinetics dictating the release of a therapeutic agent could be confidently andefficiently controlled [12]. The ability to develop specific nano-chemo agents that are underprecise directives to release the drug within the tumor in an exclusive manner is imperative forsuccessful treatment of future brain tumor patients in that it enables the clinicians to decreasethe side-effects of the chemoagent by ensuring its administration only to the cancerous tissuewithin the brain. The development of these nano-sized medicinal elements is multifaceted inthat it dictates a trajectory through basic science research, translational and clinical medicine,and industry partners (Figure 3). In a series of important experiments, Gulyaev, Kreuter andSteiniger, et al. demonstrated the successful attachment of the chemotherapeutic drug,doxorubicin, and neuropeptides to the surface of poly (butylcyanoacrylate) nanoparticles coatedwith polysorbate 80 [13-14]. Rodents treated with a doxorubicin polysorbate-coated nanoparticleshowed higher survival rates than control groups. More than 20% of animals treated with thenanoparticle-doxorubicin conjugate showed long-term remission [15]. Histologically, tumor sizein the treated group was smaller.

According to Silve, et al., the activity of polysorbate on the surfaces of the nanoparticles has twodistinct effects on the nano-chemo conjugate: 1) it enables the incorporation of apolipoproteinsB and E and 2) causes the nanoparticle to be taken up by brain capillary endothelial cells viareceptor-mediated endocytosis [8]. The development of rat glioma models has allowed for thetesting of these nanoparticle-chemoagent conjugates. Studies with these models havedemonstrated significant remission with minimal toxicity [15]. These two properties aresignificant because although a significant amount of literature is dedicated to understandinghow nanoparticles could cross the BBB, a scarce amount is reported on the molecular and cellularmechanisms by which nanoparticles manage to cross the BBB in a safe manner. Understandingthese physiological mechanisms is a prerequisite for creating safe nanoparticle-based clinicaltrials in the future. To this note, poly (butylcyanoacrylate) nanoparticles coated with polysorbate80 have been studied extensively and are now thought to be the first of a class of nanoparticleswith a known cellular mechanism of crossing the BBB. Poly (butylcyanoacrylate) nanoparticlescoated with polysorbate 80 contain apolipoproteins B and E which can naturally cross the BBBand subsequently become taken up by brain capillaries via receptor-mediated endocytosis [16-17]. The development of rodent models which can uptake nanoparticle-chemoagent conjugatesand successfully transfer these agents across the BBB and attack the tumor while demonstratingminimal toxicity paves the way for future clinical trials.

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FIGURE 3: Anticancer Nanoparticle Development

"Polymer–drug conjugates as nano-sized medicines. Adapted from Canal, et al. [18] Reused withlicensed permission: Current Opinion in Biotechnology (Elsevier license number:3335641370510): Forefront nanobiotechnology with polymer–drug conjugate.

Magnetic nanoparticles in neuro-oncology and thermo-ablation“Those diseases that medicines do not cure are cured by the knife. Those that the knife does notcure are cured by fire. Those that fire does not cure, must be considered incurable.” -Hippocrates, 370 BC [19]. Glioblastoma is currently the most recalcitrant neurological cancer totreat. Although an initial resection of the tumor is possible, the recapitulation of the tumor,fueled by cancer stem cells, yields the ultimate demise of the patient. Residual infiltrating braincancer cells are the target of a flurry of research initiatives aimed at decreasing the mortality ratein GBM patients. Particular nanobiotechnologies have emerged with potential capabilities toboth diagnose and treat glioblastomas via an intrinsic heating mechanism deployed by thenanoparticle within the brain matter (Figure 4). The basics of this intracranial heating system arebased on the peculiar paramagnetic properties of magnetic nanoparticles (MNPs) which allowsfor their detection by MRI imaging modalities [20-21]. The induction of hyperthermia to adjacentcells within the vicinity of the nanoparticle is a valuable asset of nanomedicine inneurooncology. When exposed to alternating magnetic fields, MNPs are endowed with thecapacity to induce hyperthermia [22]. The ramifications of temperatures of between 41 and 46Celsius on cellular activity are significant: heat stress results in protein denaturation andabnormal folding, as well as DNA cross-linking within the nucleus, ultimately leading toapoptosis [23]. On the macro-level of the brain, hyperthermia induction via MNPs couldpotentially lead to altered pH states, perfusion, and oxygenation of the tumor microenvironment[24-25]. Increased oxygenation to the tumor microenvironment may lead to increasedradiosensitivity in brain tumor treatment, as well as an increased efficacy of conventional braintumor chemoagents [26-28].

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FIGURE 4: Brain Tumor Imaging Illustrating Nanoparticle Within GBM

a,b: Pretreatment MRI of GBM. c,d: Hyperdense areas illustrating accumulation of magneticnanoparticle deposits. Blue lines represent 40 °C and red lines 50 °C. e,f: Reconstructed imagesusing CT/MRI techniques portraying the magnetic fluid in blue, the tumor bulk in brown, and thethermometry catheter in green. Reused with licensed permission Springer. Credit to Maeir-Hauf,et al. Department of Neurosurgery, Bundeswehrkrankenhaus Berlin [29].

The introduction of a specific alternating magnetic field (AMF) at the required amplitude andfrequency to the MNPs induce hyperthermia by heating up the targeted nanoparticles [22].Nduom, et al. analyzed the thermokinetics of the reactions which lead to thermal loss in thevicinity of brain tissue when MNPs are exposed to an AMF (Figure 5). MNPs convert magneticenergy into heat by means of dual synergetic mechanisms. As Nduom, et al. state, “Néelrelaxation is caused by rapidly occurring changes in the direction of magnetic moments relativeto crystal lattice. Brownian relaxation results from the physical rotation of MNPs within themedium in which they are placed. Both internal (Néel) and external (Brownian) sources offriction lead to a phase lag between applied magnetic field and the direction of magneticmoment, producing thermal losses” [22]. Thermotherapy via MNPs in brain tumors is a newavenue being explored by researchers worldwide to treat the most aggressive forms of braincancer, GBM included. MNPs used for the induction of hyperthermia and eventual

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thermotherapeutic applications are engineered from a variety of elemental metals, including iron(Fe), manganese (Mn), cobalt (Co), zinc (Zn), and other oxides [30-34].

FIGURE 5: Early Prototype of AMF Administration Device

Engineered prototype of AMF administration at 500kHz and amplitudes of up to 10kA/m. Reusedwith permission fm. Elsevier (Image License Number: 3336861484008). Credit to Jordan A, et al.[35].

In 2006, Jordan, et al, demonstrated the positive efficacy of thermo-ablative mechanisms in GBMmodeled rodents by employing aminosilane-coated iron-oxide nanoparticles [36]. Tumors wereinduced by implantation of RG-2-cells into the brains of 120 male Fisher rats. Tumor treatmentwas conducted using an AMF at a frequency of 100kHz and a variable field strength of 0-18 kA/m.The survival time of the rodents involved in the study was used by Jordan, et al. to measure theefficacy of MNP thermotherapy. Hyperthermia induction with MNPs led to a 4.5 foldprolongation of survival relative to controls [36]. Hauf, et al. conducted an initial clinical trialusing iron-oxide-based nanoparticles to induce thermo-ablation of glioblastomas in patientswith recurrent tumors [37]. The human clinical trial by Hauf and colleagues injected braintumors with aminosilane-coated iron-oxide nanoparticles and exposed the brain to an AMP of100 kHz. The resulting thermal loss by the MNPs located within the brain tumor demonstratedsuccessful induction of hyperthermia within the brain tumor at a temperature of 51.2 degreesCelsius [37]. Patients did not experience side-effects, such as headache and nausea, and noneurological abnormalities or infections were detected in the treated region of the brainmatter. Neuro-navigation techniques and thorough preoperative planning may be responsible forthe lack of unwanted side-effects. In each patient, the navigation-guided puncture of the tumorwas 100% successful, thereby preventing bleeding and inflammation. The median survival afterrecurrence was 13.4 months (95% CI=10.6-16.2 months) and from the time of initial diagnosiswas 23.2 months [37]. The success of this innovative clinical trial paves the way for safe andeffective thermotherapy of cancerous brain tumors with the utilization of newly engineeredMNPs (Figure 6). The overall results of this clinical trial demonstrated an increased survival ratein patients treated via thermotherapy and MNPs when compared to controls [37].

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FIGURE 6: Magnetic Nanoparticle Application

Demonstration of potential applications of magnetic nanoparticles. Reused with licensedpermission from Nature Nanotechnology (Image License number 3336880765668). CreditedPlank, et al. [38].

ConclusionsIn this review, we have presented findings to suggest that nanotechnology will serve as a viablecandidate for potential treatments of various brain cancers, reducing both untoward morbidityand mortality from this devastating disease. Magnetic nanoparticles that can be MRI-compatible might provide the ideal theranostic platform for successful thermoablation, inaddition to serving as a suitable candididate for precise drug delivery. We are encouraged, bothfrom an industry and research perspective, by ongoing studies toward the safe use ofnanomaterials for brain cancer treatment, and suggest that nanotechnology may serve as anideal conduit the enhancement of the brain tumor therapeutic paradigm.

Additional Information

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DisclosuresConflicts of interest: The authors have declared that no conflicts of interest exist.

AcknowledgementsWe would like to acknowledge Dr. Bruce Davidson, PhD and Claire Levine for their time to editand give valuable suggestions to this manuscript.

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